Our long term goal is to understand the cellular and molecular bases of immunologic tolerance. We have utilized the model system of neonatal induction of tolerance to H-2 alloantigens and have determined that the major mechanism responsible for tolerance of class I alloantigens is clonal elimination. Our recent experimental findings indicate that tolerance of class II alloantigens is dependent upon the induction of an active state of specific suppression. From these results we have formulated the hypothesis upon which the studies outlined in this proposal are based: Neonatally-induced tolerance of class II alloantigens is accomplished at least in part by an active, suppression mechanism that arrest tolerogen- reactive host T cells at a stage of antigen-induced differentiation prior to the acquisition of effector function. We propose two specific aims: 1. To analyze class II specific tolerance by examining the functional and molecular biologic properties of tolerogen-reactive cells and to determine the extent to which these properties mediate suppression and/or are responsible for clonal arrest prior to acquisition of effector function. 2. To study the resistance of I-E-negative mice to neonatal tolerance induction with Class I + I-E+ semiallogeneic hematopoietic cells. Class II-directed T cells dominate the inductive and regulatory components of immune responses. Therefore, developing an understanding of the means by which class II-directed T cells are rendered specifically non-reactive becomes an essential strategy for understanding the primary means by which the immune system is regulated. The pivotal role of class II-directed T cells in transplantation immunity, many autoimmune disorders, and in tumor immunity indicates that our experimental findings which will illuminate methods for modifying the functional potential of these cells that will be important in developing future clinical and therapeutic approaches to these important diseases to man.